Am. J. Respir. Crit. Care Med., Volume 159, Number 2, February 1999, 452-460

Inhibition of -Adrenergic Desensitization by K_Ca Channels in Human Trachealis

HIROAKI KUME and KENZO TAKAGI

Second Department of Internal Medicine, School of Medicine, Nagoya University, Nagoya, Japan

We examined the reduced responsiveness to -adrenergic receptor agonists (-agonists) after exposure to -agonists, and the mechanisms underlying this phenomenon in isolated human tracheal smooth muscle, using isometric tension records to test the hypothesis that repeated inhalation of -agonists leads to reduced responsiveness to -agonists. The inhibitory effects of isoproterenol (ISO) on contraction by spasmogens participating in asthma attacks diminished markedly after continuous exposure to ISO (0.0003 to 3 µM) for 45 min; moreover, when ISO was repeatedly applied for 10 min to tissues precontracted by methacholine every 30 min, the relaxant effects of ISO gradually attenuated after these repeated applications. In contrast, reduced -adrenergic relaxation after continuous and repeated exposure to agonists did not occur when tissues were preincubated with 2 µg/ ml cholera toxin (CTX), which irreversibly activates guanosine triphosphate (GTP)-binding protein (G_s) coupled with -adrenergic receptors, for 6 h. However, the CTX inhibition disappeared in the presence of iberiotoxin, a selective inhibitor of large conductance Ca²⁺-activated K⁺ (K_Ca) channels. Our results demonstrate that continuous and repeated exposure to -agonists leads to -adrenergic desensitization, and that activation of K_Ca channels by G_s prevents this desensitization.

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